Endogenous somatostatin receptors (SSTRs) offer novel targets for treating pain via both peripheral and central mechanisms. Our studies show that peripheral SSTR activation prevents nociceptor sensitization and provides phasic and tonic inhibitory control of nociceptors. This modulation is an important therapeutic goal since sensitization of peripheral nociceptors in inflammation defines the quality and duration of primary hyperalgesia and contributes to central sensitization and secondary hyperalgesia. Targeting peripheral SSTRs is further supported by clinical studies demonstrating analgesia following systemic administration of the SST peptide analog octreotide (OCT). The targeting of central SSTRs to treat pain is supported by several clinical studies that date back over 2 decades. Thus, intrathecal administration of native SST as well as the peptide analog OCT provides analgesia in severe pain (e.g. cancer pain) even in cases when opioids are no longer effective. Unfortunately, the potential of SST analogues for treating pain by central mechanisms has been unrealized due to poor CNS penetration of available SST peptide drugs. Our ultimate aim is to develop non-peptide SSTR agonists known as NISAs (Non-peptide Imidazolidinedione Somatostatin Agonists) as novel analgesics. Phase I studies were completed using the potent and highly SSTR2 selective NISA, SCR007. Administration of SCR007 by a local (intraplantar) or systemic (ip) route, reduced pain behaviors in vivo and peripheral sensitization of nociceptors in vitro in 2 models of acute inflammation. In Phase II, other NISA analogs with a spectrum of lipophilicities will be compounded and tested in vitro for antinociceptive properties (Aim 1). SCR007 and another promising NISA analogue (from Aim 1) will be tested in 2 models of chronic pain (Aims 2 and 3), with the aim of identifying an analgesic compound that is suitable for drug development. Using constant infusion by Alzet pumps, the anti-nociceptive effect of candidate drugs will be tested in 2 clinically relevant chronic pain models which have inflammatory components (spinal cord injury-and complete Freunds adjuvant-induced pain), via 2 routes (systemic and intrathecal). We will assess the behavioral, physiological and anatomical outcomes of NISAs treatment, evaluating their potential to yield highly desirable analgesics which could greatly reduce the current reliance on opioid therapies. [unreadable] [unreadable] [unreadable]